HCV core protein binds to gC1qR to induce A20 expression and inhibit cytokine production through MAPKs and NF-κB signaling pathways

Abstract

Hepatitis C virus (HCV) infection is characterized by a strong propensity toward chronicity. During chronic HCV infection, HCV core protein is implicated in deregulating cytokine expression that associates with chronic inflammation. A20 is known as a powerful suppressor in cytokine signaling, in this study, we explored the A20 expression in macrophages induced by HCV core protein and the involved signaling pathways. Results demonstrated that HCV core protein induced A20 expression in macrophages. Silencing A20 significantly enhanced the secretion of IL-6, IL-1β and TGF-β1, but not IL-8 and TNF. Additionally, HCV core protein interacted with gC1qR, but not TLR2, TLR3 and TLR4 in pull-down assay. Silencing gC1qR abrogated core-induced A20 expression. Furthermore, HCV core protein activated MAPK, NF-κB and PI3K/AKT pathways in macrophages. Inhibition of P38, JNK and NF-κB but not ERK and AKT activities greatly reduced the A20 expression. In conclusion, the study suggests that HCV core protein ligates gC1qR to induce A20 expression in macrophages via P38, JNK and NF-κB signaling pathways, which leads to a low-grade chronic inflammation during HCV infection. It represents a novel mechanism by which HCV usurps the host for persistence.

Decreased expression of A20 is associated with ocular Behcet’s disease (BD) but not with Vogt-Koyanagi-Harada (VKH) disease

“…Silencing of A20 caused an increased JNK and p38 activation but did not affect ERK1/2. This is similar to the results of other studies25 but differs from a study where it was found that knockdown of A20 in mesenchymal stem cells inhibited p38 MAPK pathway activation, thereby promoting TNF-α production and inhibiting IL-10 production 26. The reasons for the discrepancy may be due to the different cell types used, whereby the mesenchymal stem cell is a very special cell type, capable of self-renewal and various differentiation abilities.…”

Downregulation of A20 Expression Increases the Immune Response and Apoptosis and Reduces Virus Production in Cells Infected by the Human Respiratory Syncytial Virus

“…In line with this, it has been described that A20 promotes influenza virus replication by suppressing the antiviral response of infected cells [68]. Similarly, it has been shown that A20 promotes hepatitis C virus and human cytomegalovirus replication [69][70][71]. Additionally, the increased apoptosis observed in silenced and KO cells may have also contributed to reducing virus production.…”

Respiratory Syncytial Virus Replication Is Promoted by Autophagy-Mediated Inhibition of Apoptosis

“…Lentiviral particles were packaged by transfecting 293T cells with pSIF-H1-copGFP shRNA Expression Lentivectors (System Biosciences) and packaging vectors using Lipofectamine 2000 according to the manufacturer's instructions. The sequences used in the shRNA targeting ATG5, ATG7, BECN1, and luciferase (the control shRNA) were as follows: 5=-TCATGGAATTGAGCCAATGTT-3= (58), 5=-GCTGGATGAA GCTCCCAAGGACATT-3= (59), 5=-GGATGATGAGCTGAAGA GTGTTGAA-3= (59), and 5=-CTTACGCTGAGTACT TCGA-3= (60). Western blotting was performed to determine knockdown efficiency.…”